Neuromuscular blocking agents are a class of compounds for pharmacological use showing remarkable structural analogies because most of them are tetrahydropapaverine derivatives. Among the neuromuscular agents belonging to this class, atracurium besylate, doxacurium chloride, mivacurium chloride and gantacurium chloride, all isoquinoline derivatives, may be cited.
These compounds are prepared by synthetic route as mixtures of different geometrical and optical isomers which are particularly complicated to separate.
For example, atracurium besylate is a mixture of ten geometrical and optical isomers (Eur. J. Med. Chem.—Chim Ther., 1984-19, no. 5, pages 441-450).
Cis-atracurium besylate is one of these isomers, in particular the 1R-cis,1′R-cis isomer of formula
marketed as neuromuscular blocking agent under the tradename Nimbex®.
In WO92/00965 the preparation of cis-atracurium besylate by chromatography of (1R,1′R)-atracurium besylate, that is the mixture of the isomers cis-cis, cis-trans and trans-trans, is described.
The described chromatographic method is the high pressure liquid chromatography (HPLC) using silica or alumina as stationary phase and a suitable mixture of solvents as mobile phase. The preferred mixture of solvent is a mixture of methylene chloride, methanol, benzensulfonic acid in the ratio 4000:500:0.25.
However, by repeating the chromatographic purification method described in WO92/00965, the atracurium besylate isomer 1R-cis,1R′-cis cannot be obtained. On the contrary, degradation products of atracurium besylate are obtained, in particular the compounds likely obtained by Hoffman degradation, known as impurities C and F of atracurium besylate (European Pharmacopeia 5.2, pages 3170-3172).